title: Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1.
abstract: BACKGROUND
  The effect of transforming growth factor (TGF)-α on fibrosis varies between cell types and the role of TGF-α in hepatic fibrosis has not been fully elucidated.
  
  
  METHODS
  We examined the effect of TGF-α on hepatic fibrosis using TGF-α-expressing transgenic mice fed a methionine- and choline-deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX-2, rat and human primary HSCs.
  
  
  RESULTS
  Although the expression levels of the tissue inhibitor of metalloproteinases-1 and α1(I) collagen mRNA were unchanged, feeding the TGF-α transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase-1 (MMP-1), MMP-13 mRNA and protein and attenuated hepatic fibrosis compared with wild-type mice. TGF-α overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet-fed mice. The effect of TGF-α on the fibrogenic and anti-fibrogenic gene expressions varied between cell types in vitro. TGF-α increased MMP-1 mRNA expressions that were completely blocked by gefitinib in LX-2 cells. The extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase and p38 pathways were involved in MMP-1 mRNA expression in LX-2 cells. Although TGF-α increased the phosphorylation of p38, the p38 inhibitor activated the RAS-ERK pathway and increased TGF-α-induced MMP-1 mRNA expression, which suggested that there may be a crosstalk between the RAS-ERK and the p38 pathways in LX-2 cells.
  
  
  CONCLUSIONS
  The TGF-α may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP-1. The balance between fibrogenic and anti-fibrogenic gene expression and between the activity of the RAS-ERK and the p38 pathways may be crucial for the fibrotic process.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ohyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Ken
authors.initials: K
authors.lastname: Sato
authors.forename: Norio
authors.initials: N
authors.lastname: Horiguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002794:Choline; D017931:DNA Primers / Q000235:genetics; D004032:Diet; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051381:Rats; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017931:DNA Primers; D016211:Transforming Growth Factor alpha; D008715:Methionine; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D002794:Choline